Guanidino-alkyl-aza-spiroalkanes



United States Patent 3,326,925 GUANIDINO-ALKYL-AZA-SPIROALKANES Don Pierre Ren Lucien Giudicelli, Fontenay-sous-Bois,

and Henry Najer, Paris, France, assignors to Les Laboratoires Dausse, Paris, France, a company of France N0 Drawing. Filed May 26, 1964, Ser. No. 370,343 Claims priority, application France, May 27, 1963, 936,120; May 30, 1963, 936,591 13 Claims. (Cl. 260-293) This invention relates to spiroalkane derivatives. The invention provides guanidino-alkyl-aza-spiroalkanes of the formula:

in which k is an integer from 1 to 7, m is an integer from 0 to 3, and n is an integer from 1 to 4, the sum of k, m, and n being at least 3 and at most 8, R R R R R R R and R are each hydrogen or lower alkyl, the total number of carbon atoms in the said R radicals not exceeding 6, and A is a straight or branched alkylene radical containing 1 to 6 carbon atoms, and the acid addition salts and quaternary ammonium derivatives thereof.

The alkylene radical A in formula I is ordinarily ethylene, 1,2-propylene, 1,3-pr0pylene, 1,3 butylene, 2,3-butylene, 1,4-butylene, 1,5-pentylene, or 1,6-hexylene, especial- 1y ethylene.

These compounds have a rapid and lasting hypotensive effect, and can be satisfactorily tolerated. They are thus useful in the treatment of hypertension.

The hypotensive activity of the compounds of the invention is greater as the total number of atoms of the aza-spiro ring is nearer to 8 and as the sum 071+) is nearer to 4. Thus compounds in which the aza-s-piroalkane nucleus contains 68 carbon atoms are preferred.

Administered intravenously to a chloralosed dog in doses between 0.002 and 0.015 g./kg., the compounds of the invention cause:

(a) Slow liberation of pyrocatechol amines from their depots in the organism;

(b) More or less complete or more or less prolonged inhibition of the reflex hypertension following occlusion of the carotids;

(c) Diminution or suppression, for a period of time, of the hypertension following the excitation of the central end of the vagus nerve;

(d) More or less intense reinforcement of the hypertension induced by adrenalin or noradrenalin when these hormones are injected intravenously;

(e) Decrease in arterial blood pressure without ganglionic blockage: the rapidity, progressiveness, intensity, and duration (several hours to several days) of this effect varies with the derivative.

On the other hand, when administered intravenously to an awakened cat in a dose of 0.010 g./kg., the new compounds cause a relaxation of the nictitating membrane, of which the rapidity, intensity and duration vary from one compound to the other, the duration being in some cases as much as 100 hours or even more.

In a cat which has received intravenously 0.002 to 0.015 g./kg. of one of the new compounds, the contraction of the nictitating membrane, following the postganglionic excitation of the cervical sympathetic nervous system, is sometimes inhibited and sometimes completely suppressed, according to the nature of the compound administered. On the other hand, the sensitivity of the nictitating membrane to the intravenous injection of adrenalin or noradrenalin is greatly increased, the contraction produced by these two pyrocatechol amines being much 3 ,326,925 Patented June 20, 1967 "ice more intense after, than before, administration of the new compounds.

The compounds which are of greatest interest for therapeutic purposes include the following:

N- ,B-guanidinoethyl) -6-azaspiro- [2.5] -oct ane,

N- fl-guanidinoethyl -6-azaspiro- [3 .4] -octane,

N- (fi-guanidinoethyl -7-azaspiro- [3 .5] -nonane, N- B-guanidinoethyl -2-azaspiro- [4.4] -nonane, N- B-guanidinoethyl -8-azaspiro- [4.5 -decane, N- ,B-guanidinoethyl -2-azaspiro- [4.5 -decane, N- ,B-gu anidinoethyl -3-azaspiro- 5.5 -decane,

and their acid addition salts.

Thus, the neutral sulphate of N-(fi-guanidinoethyl)-6- azaspiro-[2.5]-octane, the method of preparation of which forms the subject of Example l(e) below, has an anti-hypertensive activity which is 1.5 to 2 times that of guanethidine. Moreover, its LD determined according to the method of Kaerber & Behrens, after intravenous administration to the white mouse, is 46 mg./kg. whereas that of gu-anethidine, according to the literature, is 23 :04 ling/kg. when administered intravenously in the rat.

The substantially normal behaviour of the cats which have received intravenously 10 mg./kg. of this compound (the dose being expressed as the base) contrasts with that of animals of the same species treated with an identical dose (expressed as base) of guanethidine. The latter remain prostrate, sleepy and anorexic during the 2 to 3 days following the injection.

The various effects described above are shown by the neutral sulphate of N-(fi-guanidinoethyl) -6- azaspiro- [2.5]-octane, when administered to the dog or cat under the influence of chloralose. These effects are rapid, durable and more intense than those shown by guanethidine.

In accordance with a feature of the invention the compounds of formula I are made by reacting together compounds of the formulae:

formula:

A-NH-C NH Preferably P is ANH and Q is RS--C(:NH), ROC(:NH), or NC- (where R is an alkyl group). That is to say, an N-(w-aminoalkyl)-aza-spiroalkane is reacted with an S-alkyl-isothiourea, an alkyl isourea, or cyanamide.

It is especially advantageous to react the N-(w-arninoalkyl)-aza-spiroalkane with S-methyl-isothiourea sulphate in an inert solvent, the molar ratio being ordinarily 2:1. Conveniently the solvent is water or an alcohol, and the reaction is continued for several hours at reflux temperature in a stream of nitrogen. The N-(w-guanidinoalkyD- aza-spiroalkane sulphate is thus obtained, from which the base can be extracted after basification. The base may easily be transformed into any pharmaceutically acceptable organic or mineral acid salt or, by addition of an alkylating agent, into a quaternary ammonium derivative.

The N-(w-aminoalkyl)-aza-spiroalkanes used as starting materials can be prepared by reduction in an inert solvent, for example ether or tetrahydrofuran, or a corresponding N-(w-cyanoalkyl)-aza-spiroalkane (in which the cyanoalkyl group is -A'CN, where A is such that -ACH is the same as A), using an appropriate reducing agent, such as lithium-aluminium hydride.

The N-(w-cyanoalkyl)-aza-spiroalkanes are themselves obtained by heating for several hours at reflux temperature equimolar quantities of a corresponding unsubstituted aza-spiroalkane and an w-halogenoalkyl nitrile in an aromatic hydrocarbon, for example benzene, in the presence of an alkali, such as potassium carbonate, to bind the hydrogen halide formed.

The unsubstituted aza-spiroalkanes are obtained by reduction of the corresponding cyclic imides, e.g. the 3,3- olymethylene-spiro-azetidine-2,4-diones, 3,3-polymethylenespiro-pyrrolidone-2,5-diones, and 3,3-polymethylenespiro-piperidine-Z,6-diones. Among the latter 3,3-dimethylenespiro-piperidine-2,6-dione (or 6-aza-spiro- [2,5 1 octane-5,7-dione) is obtained by pyrolysis at 250300 C. of the ammonium salt of cyclopropane-l,l-diacetic acid.

The process of the invention may alternatively be carried out by reacting a compound in which P is H with a compound in which Q is Hal-A-NHC(:NH) or HalA'CONHC(:NH)-, where Hal is halogen, for example by causing an w-halogenoalkyl guanidine to react with an aza-spiroalkane, or by causing an w-halogenoacyl guanidine to react with a aza-spiroalkane, followed by reduction of the CO grouping of the acylated derivative obtained to a -CH grouping, using an appropriate reducing agent, for example lithiumaluminium hydride.

The invention includes within its scope pharmaceutical compositions comprising at least one compound of the invention in association with a compatible, pharmaceutically acceptable diluent. Such compositions are more especially used in the treatment of arterial hypertension. When the active ingredient is in the form of a salt, this salt will be one derived from an acid acceptable from a pharmaceutical point of view.

The compositions are preferably in the form of tablets, dragees, or capsules, for oral administration, and may contain the new compounds alone or in association with other therapeutic agents. The following are examples of compositions within the scope of the invention.

(1) Simple composition (amounts for one tablet):

G. Salt of N-(w-guanidinoalkyl)-aza-spiroalkane (expressed as the base) 0.0005 to 0.100 Excipient.

(2) Compound compositions containing, in addition, reserpine or other alkaloid of Rauwolfia serpentina (amounts for one tablet): G

(a) Salt of N-(w-guanidinoalkyD-azaspiroalkane (expressed as the base)- 0.0005 to 0.100 Reserpine (as the hydrochloride) 0.00002 to 0.0002 Excipient.

(b) Salt of N-(w-guanidinoalkyl)-azaspiroalkane (expressed as the base)- 0.0005 to 0.100

Reserpine (as the hydro chloride) 0.000 1 Rescinnamine 0.00025 Raupine 0.00001 Ajmaline 0.00019 Methyl yohimbate 0.0006 Excipient.

The following example and the data in the table illustrate the invention.

4 EXAMPLE Preparation of N-(B-guanidinoethyl)-6-azaspir0- [2,51-0ctane (a) 6-azaspir0-[2,5]-0ctane-5,7-di0ne.-In a spherical Claisen flask with a capacity of cc., equipped with a sealed-in capillary tube and a coil-type condenser and double jacket, there is placed 31.6 g. (0.2 mol/g.) of cyclopropane-1,1-diacetic acid in suspension in 30 cc. of water. Ammonia is bubbled through the capillary tube until complete dissolution has occurred. The flask, the contents of which are kept under a stream of ammonia, is then introduced into a metal bath preheated to 90 C. and heating is continued for 30 minutes at to C. until the water has completely evaporated. The temperature of the bath is then brought to 250 to 260 C., and this temperature is maintained for 35 minutes. After 20 minutes, the ammonium salt melts, and then dehydrates. The contents of the flask are allowed to cool, and are then dissolved in 250 cc. of boiling ethyl acetate. The solution is filtered through Norit, cooled in ice, and filtered. The residue is washed with ethyl acetate and dried in vacuo. 9.9 g. (yield=35.6%) of 6-azaspiro-[2.5]-octane- 5,7-dione are obtained, soluble in alcohols and sparingly soluble in ether, melting point= C.

Analysis.-C H NO (M.W.=139). Calculated, percent: C, 60.43; H, 6.47; N, 10.07. Found, percent: C, 60.56, 60.71; H, 6.41, 6.46; N, 9.96, 9.99.

(b) 6-azaspiro-[2.5]-0ctane.1nto a l-litre spherical flask having 2 tubulures, equipped with a mechanical stirrer and a Soxhlet extractor containing 35.7 g. (0.257 mol/g.) of 6-azaspiro-[2,5] octane 5,7 dione, above which is condenser equipped with a calcium chloride trap, are introduced 19.5 g. (0.51 mol/g.) of lithiumaluminium hydride in 500 cc. of anhydrous ether. While the ether is refluxed for 8 hours the dione is progressively brought into contact with the reducing agent. The reduction is terminated by heating under reflux for 5 /2 hours, the mixture is then cooled to 0 C., and hydrolysed by successively adding 20 cc. of water, 15 cc. of 15% sodium hydroxide and 70 cc. of water. The mineral salts are filtered off and washed three times with ether. The ethereal solution is dried overnight over potassium carbonate and filtered, the ether is driven ofi, and the liquid residue is distilled in vacuo. 18.5 g. (yield=65%) of 6- azaspiro-[2.5]-octane, distilling at 59 to 60 C./4 mm., are obtained as a colourless liquid soluble in the alcohols, benzene, and ether, and forming a carbonate very rapidly in air; n =1.4672.

Analysis.C H N; (M.W.=111). Calculated, percent: C, 75.68; H, 11.71. Found, percent: C, 73.30, 73.35; H, 12.25, 12.15.

(The too low results with carbon and too high results with hydrogen are due to the avidity of the compound for carbon dioxide and the humidity of the air.) The tliicsrate of the base, recrystallised from alcohol, melts at (c) N-cyanomezhyl-fi-azaspiro-[2,5] -0ctane.In a 1- litre flask having 3 tubulures, equipped with a dropping funnel, a mechanical stirrer and a condenser, are introduced 14.5 g. (0.192 mol/ g.) of chloracetonitrile, 10.2 g. (0.095 mol/ g.) of sodium carbonate and 250 cc. of benzene. By the dropping funnel, a solution of 17.8 g. (0.16 mol/g.) of 6-azaspiro-[2,5]-octane in 100 cc. of benzene is slowly poured in, 0.5 cc. of water is then added, and the mixture is heated for 5 hours under reflux with stirring. The mineral salts are centrifuged off, washed twice with benzene, and the benzene solution is dried overnight over sodium sulphate and filtered. The benzene is driven ofi on a water bath, and the residue is then distilled in vacuo. 21 g. (yield=87.5%) of N-cyanomethyl-6-azaspiro-[2.5]-0ctane are recovered as a colourless liquid, distilling at 83 C./12 mm., and soluble in the conventional organic solvents; n =1.4805.

Analysis.C H N (M.W.=l50). Calculated, per- 5 cent: C, 72.00; H, 9.33. Found, percent: C, 71.41, 71.36; H, 9.44, 9.39.

(d) N-(B-aminoethyl)-6-azaspiro-[2.5] ctane.--Into a 2-litre spherical flask having 3 tubulures, equipped with a dropping funnel, a condenser surmounted by a calcium 5 chloride trap and a mechanical stirrer, a suspension of 5.3 g. (0.138 mol/g.) of lithium-aluminium hydride in 500 cc. of anhydrous ether is introduced, and the contents of the flask are cooled by a bath of ice and salt to below 0 C. A solution of 20.8 g. (0.138 mol/g.) of N-cyanomethyl--azaspiro-[2.5]-octane in 100 cc. of anhydrous ether is slowly poured in through the dropping funnel, while the mixture is stirred, the speed of addition being regulated so as to keep the temperature of the mixture below 0 C. The duration of the addition is 15 minutes. The mixture is left for 2 hours with stirring in the ice bath, and then for 1 hour at ambient temperature, the contents of the flask are then again cooled to below 0 C., and hydrolysed by the successive addition of 7 cc. of water, 4 cc. of 20% sodium hydroxide and 22 cc. of water. The mineral salts are centrifuged 011, carefully washed three times with ether and then three times with tetrahydrofuran. The ether tetrahydrofuran solution is dried for a few hours over potassium carbonate and filtered. The solvents are driven off and the residue is distilled in vacuo. 18.2 g. (yield=88.5%) of N(fi-aminoethyl)-6-azaspiro- [2.5]-octane are obtained as a colourless liquid distilling at 62 C./1 mm., soluble in the conventional organic solvents; n =1.4842.

Analysis.-C H N (M.W.=154). Calculated, percent: C, 70.13; H, 11.69. Found, percent: C, 70.16, 70.01; H, 11.37, 11.17.

The dipicrate, recrystallised from water, melts at 243- 244" C.

(e) N-(fi-guanidinoethyl)-6-azaspir0 [2.5] octane- In a l-litre spherical flask having 3 tubulures, equipped with a condenser and a mechanical stirrer a mixture of 10.5 g. (0.068 mol/g.) of N-(B-aminoethyl)-6-azaspiro- [2.5]-octane and 9.5 g. (0.034 mol/ g.) of S-methylisothiourea sulphate in cc. of water is refluxed for 1 hour, 40 minutes in a stream of nitrogen while stirring. The solution is evaporated to dryness; the solid residue is triturated in acetone, centrifuged and dried in vacuo. There are obtained 15.4 g. (yield=92.5%) of the neutral sulphate of N-(fi-guanidinoethyl)-6-azaspiro [2.5] octane which, when recrystallized from 450 cc. of alcohol, is obtained as a white, crystalline compound soluble in Water, M.P. 275277 C., with decomposition.

Analysis.--C H N O S; (M.W.=490). Calculated, percent: C, 48.98; H, 8.57. Found, percent: C, 48.98, 49.14; H, 8.64, 8.56.

The dihydrobromide, recrystallised from isopropyl alcohol, melts at about 150 C. (indefinite).

Using the methods employed in this example, compounds of the invention are prepared in which m is 2, the symbols R R R R R R R and R each represent hydrogen, and A represents the (CH group. These compounds, obtained as the sulphates, thus conform to the formula:

which also contains details of the intermediates.

Analyses k n B.P., C./mm. [M.P., C.] 92,, Yield, Recrystallisation percent solvent Percent 0 Percent H Found Found (calc.) (c2110.)

Final products 3 1 [250 with decomposition] 69. 5 Methyl alcohoL. 51. 8.97

' (50. 97) (8. 88) 3 2 [320 with decomposition] 95% alcohol"... 52.09 9. 19

(52. 75) (9. l6) 2 2 [310-315 with decompositionL. 76 d0 50. 56

(50. 97) (8. 88) 4 2 [335-340 with decomposition] 98 90% alcohol"--. 54.92 9.

(54. 36) (9. 41) 2 1 [237-238] B 88. 5 Alcohol 48. 82 8.54

(48. 98) (8. 57) 4 1 [260 with dec0mpositi0n] 78 Water 52. 36 9. 37

Intermediates of formula (0H2)k\ (CHM /O\ /N(CH2)2-NH; CH; (0512)..

Intermediates of 'formula (CH2) k\ 2) 2 C\ /NCH,C N CH2 112)..

Analyses k 'n B.P., C./mm. [M.P., 0.] a Yield. Recrystallisatlon percent solvent Percent C Percent H Found Found (calc.) (calc) Final products 3 1 90 91/1 1. 4815 80 72. 82 9. 75

(73. 17) (9. 76) 4 2 124/1-2 [55] 86. 5 Acetone-water. 75. 65 10. 38

Intermediates of tormula Its dihydrochloride melts at 218219 O. (recrystallised from alcohol); percent 01 (calc.)=23.9l; percent Cl (iound)=23.72.

b Its dihydrochloride melts at 243-245 C. (recrystallised from alcohol); percent 01 (calc.) =22.83; percent Cl (found)=22.5.

We claim:' 1. A compound of the formula:

in which k is an integer from 1 to 7, m is an integer from 0 to 3, and n is an integer from 1 to 4, the sum of k, m, and n being at least 3 and at most 8, each of R R R R R R R and R is selected from the class consisting of hydrogen and lower alkyl and the total number of carbon atoms in the said R radicals is at most 6, and A is an alkylene radical containing 1 to -6 carbon atoms, and the pharmaceutically acceptable acid addition salts and quaternary ammonium derivatives thereof.

2. A compound as claimed in claim 1 R radicals are hydrogen.

3. A compound as claimed in claim 1 in which A is selected from the class consisting of ethylene, 1,2-propylone, 1,3-propylene, 1,3-butylene, 2,3-butylene, 1,4-butylene, 1,5-pentylene, and 1,6-hexylene.

4. A compound as claimed in claim 1 in which the azaspiroalkane nucleus contains 6 to 8 carbon atoms.

5. A compound of the formula:

in which all the Its dihydrobromide, recrystallised from a mixture of methyl ethyl ketone and isopropyl alcohol (1:1) is hygroscopic; percent Br. calc.= 44.69; percent Br. found=44.77.

The too low carbon content is due to the avidity of this amine for the carbon dioxide of the air. in which k is 1 to 4, and n is 1 to 2, and its acid addition salts.

6. A compound as claimed in claim 5, in which the sum of k and n is at most 4.

7. N-(fl-guanidinoethyl) -6-azaspiro-[2.5] -octane and its pharmaceutically acceptable acid addition salts.

8. N-(fi-guanidinoethyl)-8-azaspiro-[4.5] decane its pharmaceutically acceptable acid solution salts.

9. N-(B-guanidinoethyl)-7-aZaspiro-[3.5] nonane its pharmaceutically acceptable acid addition salts.

10. N-(fl-guanidinoethyl)-2-azaspiro-[4.4]-nonane its pharmaceutically acceptable acid addition salts.

11. N- ,B-guanidinoethyl) -2-azaspiro- [4.5 -decane its pharmaceutically acceptable acid addition salts.

12. N- (B-guanidinoethyl) -3-azaspiro- [5.5] -decane its pharmaceutically acceptable acid addition salts.

13. N-(fi-guanidinoethyl)-6-azaspiro-[3.4] octane its pharmaceutically acceptable acid addition salts.

and

and

and

and

and

and

References Cited UNITED STATES PATENTS 3,078,272 2/1963 Mull 260293 3,106,552 10/1963 Grogan 260293 3,189,601 6/1965 Mull 260-32686 3,200,118 8/1965 Grogan 260-293 WALTER A. MODANCE, Primary Examiner.

JOHN D. RANDOLPH, Examiner. AVROM D. SPEVACK, Assistant Examiner. 

1. A COMPOUND OF THE FORMULA:
 7. N-(B-GUANIDINOETHYL)-6-AZASPIRO-(2.5)-OCTANE AND ITS PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS. 